This Article Full Text Full Text (PDF) Supplemental Data Tables All Versions of this Article: 20/3/675    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clarkson, R. W. E. Articles by Watson, C. J. Search for Related Content PubMed PubMed Citation Articles by Clarkson, R. W. E. Articles by Watson, C. J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH

The Genes Induced by Signal Transducer and Activators of Transcription (STAT)3 and STAT5 in Mammary Epithelial Cells Define the Roles of these STATs in Mammary Development

Department of Pathology (R.W.E.C., M.P.B., E.A.K., P.G.T., C.J.W.), University of Cambridge, Cambridge CB2 1QP, United Kingdom; and Medical Research Council-Rosalind Franklin Centre for Genome Research (J.M.L., T.C.F.) Hinxton, Cambridge CB10 1SB, United Kingdom

Address all correspondence and requests for reprints to: Dr. C. J. Watson, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom. E-mail: cjw53{at}mole.bio.cam.ac.uk.

Prolactin and leukemia inhibitory factor (LIF) have different roles in the adult mammary gland, which are mediated in part by the signal transducers and activators of transcription (STAT)5 and STAT3. In vivo studies have shown that STAT5 contributes to prolactin-dependent lobuloalveolar development and lactation whereas STAT3 mediates LIF-dependent epithelial apoptosis during postlactational involution. To understand the molecular basis of these STAT-dependent pathways, we demonstrate the ligand-independent effects of STAT5 and STAT3 in mammary epithelial cells in vitro and also identify the genes regulated by these related transcription factors. Thus, using conditionally active STAT3- or STAT5a-GyraseB fusion proteins, we observed that enforced and specific dimerization of STAT3 induced apoptosis whereas STAT5 induced differentiation of mammary epithelial cells. Furthermore, STAT5 attenuated apoptosis mediated by LIF, the physiological inducer of STAT3. Microarray analysis of STAT3- and STAT5-induced genes using this system demonstrated a marked specificity, which reflected their different physiological effects in vitro and in vivo. STAT5-specific gene targets included the milk protein genes -casein and kallikrein-8 and the survival factors prosaposin and Grb10. STAT3-specific genes included the apoptosis regulators CCAAT enhancer binding protein-, phosphatidylinositol 3-kinase-regulatory subunits, purine nucleoside phosphorylase, and c-fos. These data illustrate that specific activation of STAT3 and STAT5 alone is sufficient to induce and suppress apoptosis, respectively, and that these transcription factors elicit their actions by inducing distinct subsets of target genes in mammary epithelial cells.

This article has been cited by other articles:

				K. M. Mohankumar, J. K. Perry, N. Kannan, K. Kohno, P. D. Gluckman, B. S. Emerald, and P. E. Lobie Transcriptional Activation of Signal Transducer and Activator of Transcription (STAT) 3 and STAT5B Partially Mediate Homeobox A1-Stimulated Oncogenic Transformation of the Immortalized Human Mammary Epithelial Cell Endocrinology, May 1, 2008; 149(5): 2219 - 2229. [Abstract] [Full Text] [PDF]

				M. Snyder, X.-Y. Huang, and J. J. Zhang Identification of Novel Direct Stat3 Target Genes for Control of Growth and Differentiation J. Biol. Chem., February 15, 2008; 283(7): 3791 - 3798. [Abstract] [Full Text] [PDF]

				J. Iyer and N. C. Reich Constitutive nuclear import of latent and activated STAT5a by its coiled coil domain FASEB J, February 1, 2008; 22(2): 391 - 400. [Abstract] [Full Text] [PDF]

				K. Sakamoto, B. A. Creamer, A. A. Triplett, and K.-U. Wagner The Janus Kinase 2 Is Required for Expression and Nuclear Accumulation of Cyclin D1 in Proliferating Mammary Epithelial Cells Mol. Endocrinol., August 1, 2007; 21(8): 1877 - 1892. [Abstract] [Full Text] [PDF]

				Y. Lu, S. Fukuyama, R. Yoshida, T. Kobayashi, K. Saeki, H. Shiraishi, A. Yoshimura, and G. Takaesu Loss of SOCS3 Gene Expression Converts STAT3 Function from Anti-apoptotic to Pro-apoptotic J. Biol. Chem., December 1, 2006; 281(48): 36683 - 36690. [Abstract] [Full Text] [PDF]